Nicotine inhibits cisplatin-induced apoptosis in NCI-H446 cells

Abstract

Nicotine is not only a major component in tobacco but is also a survival agonist that inhibits apoptosis induced by certain agents including chemotherapeutic drugs. Here, we first showed that nicotine inhibits cisplatin-induced apoptosis in NCI-H446 cells. An MTT assay, Annexin V-FITC staining, RT-PCR, and Western blot were applied to identify the viability of cells, stages of apoptosis, mRNA and signaling proteins expression, respectively. First, we observed that nicotine induced no significant apoptosis when used alone and promoted cell proliferation at a low concentration or for a short time, but the opposite was observed at a high concentration or for a long time. In addition, an increase in XIAP and Survivin mRNA or protein was observed. Next, when combined with cisplatin, growth inhibition rates were concentration dependent, decreased to the lowest level at first, but later climbed to the highest point. Furthermore, nicotine inhibited apoptosis induced by cisplatin and caused a concentration-dependent increase in both XIAP and Survivin mRNA or protein. Moreover, the apoptotic effect of the combination group was obviously higher than that of nicotine used alone at the same nicotine concentration and lower than that of cisplatin used alone at the same cisplatin concentration. These studies suggest that exposure to nicotine might negatively impact the apoptotic potential of chemotherapeutics.

Nicotine-Mediated Cell Proliferation and Tumor Progression in Smoking-Related Cancers

“…While tobacco smoke carcinogens initiate tumors, the current literature raises the possibility that nicotine additionally confers a survival advantage to already initiated tumors (28, 57, 65, 66) by promoting cell cycle progression and by preventing apoptosis (66, 67). This is of particular concern in the context of tobacco smoke components conferring resistance to chemotherapeutic drugs (66, 67) as well as radiation (68).…”

“…This is of particular concern in the context of tobacco smoke components conferring resistance to chemotherapeutic drugs (66, 67) as well as radiation (68). Multiple studies have reported that patients who smoke demonstrate poor response to cancer chemotherapy, and have worse prognosis than their non-smoking counterparts (65, 69, 70).…”

“…Exposure of multiple NSCLC cells to 1 µM nicotine conferred resistance to apoptosis induced by cisplatin, gemcitabine and taxol (57). It was found that exposure to nicotine led to an increase in the levels of inhibitor of apoptosis proteins (IAPs) XIAP and survivin in a α3β4 nAChR dependent manner, downstream of AKT signaling (57, 66); interestingly, nicotine did not induce cIAP1 or cIAP2 (57). AKT mediated phosphorylation is known to prevent the ubiquitination and degradation of XIAP (76); reduced ubiquitination and stabilization of XIAP was observed upon nicotine stimulation, correlating with reduced apoptosis (77).…”

Nicotine induces resistance to erlotinib via cross-talk between α 1 nAChR and EGFR in the non-small cell lung cancer xenograft model

“…In addition, about one-third of patients with lung cancer continue to smoke after diagnosis [2], not to mention non-smokers patients with lung cancer exposed to second-hand smoke. Recently, evidence for an increasing treatment-resistance associated with cigarette smoke exposure has been emerging [3,4].…”

Potential Use of Nicotinic Receptor Agonists for the Treatment of Chemotherapy-Induced Cognitive Deficits

“…' Because nAChR agonists exert neuroprotective and neurotrophic actions, an important consideration in treating chemotherapy-induced cognitive deficits with specific nAChR agonists is the impact of the agonist on the effectiveness of the chemotherapy. Studies indicate that exposure of cells to nicotine in vitro attenuates the antiproliferative activity of several chemotherapeutic agents, including etoposide, doxorubicin, gemcitabine, cisplatin and taxol [182][183][184][185][186][187][188]. Although nicotine appears to reduce the efficacy of these chemotherapeutic drugs, the specific nAChRs involved in this effect have not been established.…”